1. Field of the Invention
The present invention relates to novel prostaglandin I.sub.2 (PGI.sub.2) derivatives exhibiting excellent in vivo duration and activities.
2. Description of the Prior Art
Prostaglandin I.sub.2 (PGI.sub.2, prostacyclin) represented by the formula: ##STR2## was first found by J. R. Vane et al. in 1976. PGI.sub.2 is biosynthesized from arachidonic acid via endoperoxide (PGH.sub.2 or PGG.sub.2) in the vascular wall. It should be noted that PGI.sub.2 shows potent platelet aggregation-inhibiting and gastric acid secretion-inhibiting activities and a potent peripheral blood vessel-dilating activity: refer to C & EN, Dec. 20, 1976, page 17; and S. Moncada, R. Gryglewski, S. Bunting, and J. R. Vane, Nature, 263, 633 (1976).
PGI.sub.2 is extremely unstable even in neutral aqueous solutions due to the unstable exo-enol structure thereof and readily converted to 6-oxo PGF.sub.1.alpha. which is substantially physiologically inactive. Such instability of PGI.sub.2 is a great obstacle to its use as a drug. Furthermore, PGI.sub.2 is unstable in vivo as well and disadvantageously shows only short duration of physiological activities in vivo.
Many studies have been made on various derivatives for the purpose of improving the chemical stability and duration of activities in vivo of PGI.sub.2.
The present inventors have also studied and solved this problem of chemical instability of PGI.sub.2 by providing novel derivatives of PGI.sub.2 having a cyclopenta[b]benzofuran ring in which the exo-enol structure contributing to the instability is incorporated into the phenyl ring. Thus, the present inventors have attained a series of inventions and filed a number of patent applications: refer to Ohno et al., Japanese Patent Application Laying-Open Nos. 56-36477, 57-32277, 57-144276, 58-124778 and 59-134787.
However, the derivatives of PGI.sub.2 provided by these prior inventions are still unsatisfactory with respect to the in vivo duration and potency of activities. In particular, one of the serious disadvantages concerning the drug duration is the tendency to be converted into carboxylic acids in which the number of carbon atoms is reduced by 2 through .beta.-oxidation, one mode of the metabolism of fatty acids in vivo.
On the basis of this fact, the present inventors have made great efforts and finally achieved the present invention by devising a new structure capable of essentially inhibiting the metabolism through .beta.-oxidation.
The compounds provided according to the present invention are more excellent with respect to the duration as compared to those of the prior inventions by the present inventors. Moreover, they have more potent activities.
It is a primary object of the present invention to solve such a problem in the prior art.
Thus, an object of this invention is to provide novel PGI.sub.2 derivatives which show excellent duration of activities in vivo.
Other objects and advantages of this invention will be apparent from the description hereinbelow.